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Endocannabinoid signalling and the deteriorating brain

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Abstract

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls - and is affected by - normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.

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... The primary function of the endocannabinoids is to fine-tune neurotransmitter release, thus modulating synaptic efficacy and neuronal activity. Their wide distribution in the CNS suggests that endocannabinoids may play multiple functions, including the control of movement, memory and learning, nociception, reward processes, emotionality and anxiety, neurogenesis, and neuroinflammation [161]. Indeed, an upregulated endocannabinoid system has been observed in dogs with inflammatory CNS diseases, thus suggesting the endocannabinoid system might be a potential therapeutic target in neuroinflammationassociated disorders [162]. ...
... The endocannabinoidome comprises several lipid ligands classified according to their chemical structures in N-acylethanolamines and monoacylglycerols. These molecules are further sub-classified in endocannabinoids (i.e., agonists at CB1 and CB2 cannabinoid receptors, such as the arachidonic acid derivatives AEA and 2-AG) and endocannabinoid congeners being inactive at cannabinoid receptors (such as PEA and several similar compounds not discussed in the present review [161]). Endocannabinoid congeners are biologically active and share with AEA and 2-AG their biosynthetic and inactivating enzymes, even if they do not activate CB1 and CB2 receptors. ...
... The most studied receptors are transient receptor potential vanilloid type 1 channel (TRPV1), peroxisome proliferator-activated receptor (PPAR)-γ and -α, and two orphan G-protein coupled receptors, GPR55 and GPR18 [174]. This expanded endocannabinoid system has been called the endocannabinoidome [161]. Figure 5 schematically describes the endocannabinoidome. ...
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Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.
... The CB2 receptor is more prevalent in the periphery, particularly within immune cells [21] including those of the brain (microglia), but its expression in neurons and functions on anxiety behaviors are still enigmatic [24]. Because eCBs act on different receptors located in specific cell types, with vastly different biological activities, some of which produce and release different hormones and molecules, the eCBs are multifunctional and regulate, among others, energy balance, inflammation, and behavior [11,13,25,26]. They are pivotal molecules in synaptic excitatory (glutamatergic) and inhibitory (GABAergic) transmission of neurons and glial cell activity in the CNS [24,25] (Figure 1). ...
... Because eCBs act on different receptors located in specific cell types, with vastly different biological activities, some of which produce and release different hormones and molecules, the eCBs are multifunctional and regulate, among others, energy balance, inflammation, and behavior [11,13,25,26]. They are pivotal molecules in synaptic excitatory (glutamatergic) and inhibitory (GABAergic) transmission of neurons and glial cell activity in the CNS [24,25] (Figure 1). CB1 and CB2 are not the only receptors whose activity are responsive to AEA and 2-AG, as both ligands are able to modulate TRPV1, PPARG, and, not without controversy, GPR55 [26]. ...
... Indeed, the bimodal effect of eCB signaling in feeding behavior can either promote energy storage and fat accumulation for survival, facilitating the consumption of rewarding and palatable food, or conduct to a lack of appetite depending on the tissue concerned and the dose of eCBs [23]. Even if CB1 activation in the hypothalamus has been previously associated with orexigenic effects, specifically with the inhibition of energy expenditure in obese and older animals, this statement is not as accurate when assessing CB1 signaling counter-effect on neuroinflammation in lean animals [25]. Chronic physical activity could help control CB1 expression favorably by promoting HPA maintenance and immune homeostasis [25,60]. ...
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Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders.
... However, after the identification of the main components of cannabis and the discovery that the endocannabinoid system (ECS) is able to modulate different processes in pain medicine and psychiatric disorders, interest in the use of cannabinoids has been renewed [10,12,13,18,26]. The medical use of cannabis extracts was approved in June 2010 by ten European countries [7]. ...
... M sucrose layers [2]. The protein concentration was evaluated by the Lowry method [14], the inorganic phosphorus by the modified Fiske-Subbarow [4], and the Kazanova-Maslova method [7]. The Na, K-ATPase activity (V) was assessed as the ouabain-sensitive part of the total ATPase activity, in µmolP i h -1 (mg protein) -1 . ...
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Over the past two decades, numerous tools have been developed to study the endocannabinoid system. Studies show the potential effectiveness of endocannabinoids for the relief of pain and neurological disorders. However, global targeting of the endocannabinoid system has also been associated with unwanted outcomes, including deleterious effects on cognitive and emotional functions, the development of tolerance and dependence, and withdrawal symptoms after drug cessation in humans. The main objective of the present study was to determine whether male mice develop tolerance to delta-9-tetrahydro-cannabinol (THC) and cannabinolic acid (CBNA)-induced antinociception with long-term treatment. Using behavioral tests of mechanical and thermal nociception, we found that systemic (intraperitoneal, i.p.) administration of THC and CBNA resulted in strong antinociception on the first day of the experiment. However, over the next four days, the behavior indices of antinociception to mechanical and thermal stimuli gradually decreased, indicating the development of tolerance following systemic administration of these drugs. Thus, the two main components of cannabis, THC and CBNA, are characterized by the development of tolerance in mice as a result of their repeated i.p. administration.
... The most vital molecules are 2-arachidonoyl-glycerol (2AG) and its isomer 1AG among monoacyl-glycerols; palmitoyl-ethanolamide (PEA); oleyl-ethanolamide (OEA), and the N-acyl-ethanolamides [16][17][18]. The cannabinoid receptor type-1 and type-2, both 2AG and AEA are engaged in different biological functions; however, the AEA metabolism and attachment of the peroxisome proliferator-activated receptor-α is influenced by PEA and OEA [8,[19][20][21][22][23]. These all biomolecules are explained in detail in the endocannabinoid related compounds. ...
... Partial or full agonists of CB 1 receptors in terms of anandamide depend on tissue and biological response type. However, CB 2 receptors can attach but have an intermittent effect and can perform like an antagonist [19,20,24]. ...
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In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB 1); cannabinoid receptor 2 (CB 2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer-both in vivo and in vitro clinical trials-has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.
... Moreover, granule cell to Purkinje cell synaptic transmission can trigger endocannabinoid release (Alger and Kim, 2011), which may be important for information processing by cerebellar molecular layer interneurons (Dorgans et al., 2019). This suggests that endocannabinoids could be essential to neurocognitive aspects of cerebellar function (Di Marzo et al., 2015), (Marcaggi, 2015), (Alger and Kim, 2011), and CB1 receptor downregulation in long-term chronic cannabis use may promote CUD (Hirvonen et al., 2012). Accumulating evidence also suggests cerebellar modulation of the reward circuitry and social behavior via direct cerebellar innervation of the ventral tegmental area (VTA), including dopamine cell bodies (A1) in the VTA (Carta et al., 2019). ...
... Therefore, there is a critical need to determine how the cerebellum modulate limbic VTA-DA signaling since endocannabinoid system is essential to cerebellar function. Here, CUD related cerebellar dysfunction is postulated that can include reward-related behaviors, information processing, and cognitive control (Di Marzo et al., 2015), (Marcaggi, 2015), (Alger and Kim, 2011). ...
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Background: Maladaptive neuroplasticity related learned response in substance use disorder (SUD) can be ameliorated using non-invasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on competing neurobehavioral decision systems model. Next objective was to conduct computational simulation of NIBS of cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD) related dysfunctional “cue-reactivity” – a closely related construct of “craving” that is a core symptom. Our third objective was to test the feasibility of our neuroimaging guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG), metrics of sensorimotor gating. Therefore, we conducted computational simulation of NIBS, including transcranial direct current stimulation(tDCS) and transcranial alternating current stimulation(tACS) of the cerebellar cortex and deep cerebellar nuclei(DCN), of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging guided NIBS approach for cerebellar lobule (VII) and prefrontal cortex based on healthy human study. Results: Simulation study of cerebellar tDCS induced gamma oscillations in the cerebral cortex while tTIS induced gamma-to-beta frequency shift. Experimental fNIRS study found that 2mA cerebellar tDCS evoked similar oxyhemoglobin(HbO) response in-the-range of 5x10-6M across cerebellum and PFC brain regions (=0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO driven(phase-amplitude-coupling, PAC) 4Hz, ±2mA (max.) cerebellar tACS evoked HbO in-the-range of 10-7M that was statistically different (=0.01) across those brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC as well as fNIRS-driven ctACS at 4Hz that may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging.
... Monoacylglycerol lipase (MAGL) is a serine hydrolase that tightly regulates 2-AG-mediated neurotransmission in the eCS, and is identified not only in pre-synaptic terminals, but also in postsynaptic terminals and astrocytes [9,10]. Several reports demonstrated that treatment with MAGL inhibitors afforded neuroprotective effects in experimental ischemia models [11,12]. ...
... Taken together, the dysfunctions in neurons had occurred by two days after the MCAO surgery, when microglial activation was still gentle, and the neuroinflammation process subsequently became more aggressive from day 4 to day 7 after cerebral ischemia-reperfusion injury. More importantly, it was demonstrated that MAGL is not expressed in activated microglial cells, a finding that corresponds with previous research [9,10]. Therefore, PET with [ 11 C]SAR127303 allowed normal and abnormal conditions to be distinguished in neurons in the acute phase of cerebral injury. ...
Article
Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [11C]SAR127303 for MAGL and [18F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [11C]SAR127303 showed an acute decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 ± 0.04 in the cortex and 0.73 ± 0.02 in the striatum). PET imaging with [18F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 ± 0.11), and further increases on day 4 (1.72 ± 0.15) and day 7 (1.99 ± 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [11C]SAR127303 for MAGL (minocycline-treated group: 0.82 ± 0.06 in the cortex and 0.81 ± 0.05 in the striatum; KML29-treated group: 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum) and increased uptake of [18F]FEBMP for TSPO (minocycline-treated group: 1.52 ± 0.21 in the cortex and 1.56 ± 0.11 in the striatum; KML29-treated group: 1.63 ± 0.09 in the cortex and 1.50 ± 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia.
... The endocannabinoid system is influenced by age. For example, CB1 receptor binding and gene expression decline with age in the cerebral cortex, limbic structures, and hippocampus in animal models (Berrendero et al., 1998) and humans (Di Marzo et al., 2015). Some researchers argue that the endocannabinoid system directly controls aspects of the aging process, such that CB receptors control the cellular processes of age-related inflammation, and that age-related declines in CB1 and endocannabinoid levels induce the declines in cognition common in old age (Di Marzo et al., 2015). ...
... For example, CB1 receptor binding and gene expression decline with age in the cerebral cortex, limbic structures, and hippocampus in animal models (Berrendero et al., 1998) and humans (Di Marzo et al., 2015). Some researchers argue that the endocannabinoid system directly controls aspects of the aging process, such that CB receptors control the cellular processes of age-related inflammation, and that age-related declines in CB1 and endocannabinoid levels induce the declines in cognition common in old age (Di Marzo et al., 2015). These arguments are bolstered by animal studies showing that adult, but not juvenile, CB1-null mice perform worse than wild-type mice in a variety of cognitive studies. ...
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Several lines of evidence suggest that older adults (aged 65+) sharply increased their cannabis use over the last decade, highlighting a need to understand the effects of cannabis in this age group. Pre-clinical models suggest that cannabinoids affect the brain and cognition in an age-dependent fashion, having generally beneficial effects on older animals and deleterious effects on younger ones. However, there is little research on how cannabis affects the brains of older adults or how older adults differ from younger adults who use cannabis. Resting state functional connectivity (rsFC) measures provide sensitive metrics of age-related cognitive decline. Here we compared rsFC in older adults who are either regular users of cannabis or non-users. We found stronger connectivity between sources in the hippocampus and parahippocampal cortex, and targets in the anterior lobes of the cerebellum in older adult cannabis users relative to non-users. A similar pattern of strengthened connectivity between hippocampal and cerebellar structures was also present in 25–35 year old non-users in comparison to 60–88 year old non-users. These findings suggest that future studies should examine both the potential risks of cannabinoids, as well as a potential benefits, on cognition and brain health for older adults.
... In the context of increasing cannabis legalization in the United States and elsewhere, and cannabis use is becoming increasingly common among older adults (Han and Palamar, 2020). Notably, however, eCS signaling declines with age (Di Marzo et al., 2015), and there is limited research on the neural and health impacts of cannabis use among older adults. It is also relevant to note that chronically-administered THC may reverse age-related cognitive impairment in animal models (Bilkei-Gorzo et al., 2017). ...
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Background : Exploring biological variables that may serve as indicators of the development and progression of cognitive decline is currently a high-priority research area. Recent studies have demonstrated that during normal aging, individuals experience increased inflammation throughout the brain and body, which may be linked to cognitive impairment and reduced gray matter volume in the brain. Neurofilament light polypeptide (NfL), which is released into the circulation following neuronal damage, has been proposed as a biomarker for neurodegenerative diseases, and may also have utility in the context of normal aging. The present study tested associations between age, peripheral levels of the pro-inflammatory cytokine IL-6, peripheral NfL, brain volume, and cognitive performance in a sample of healthy adults over 60 years old. Methods : Of the 273 individuals who participated in this study, 173 had useable neuroimaging data, a subset of whom had useable blood data (used for quantifying IL-6 and NfL) and completed a cognitive task. Gray matter (GM) thickness values were extracted from brain areas of interest using Freesurfer. Regression models were used to test relationships between IL-6, NfL, GM, and cognitive performance. To test putative functional relationships between these variables, exploratory path analytic models were estimated, in which the relationship between age, IL-6, and working memory performance were linked via four different operationalizations of brain health: (1) a latent GM variable composed of several regions linked to cognitive impairment, (2) NfL alone, (3) NfL combined with the GM latent variable, and (4) the hippocampus alone. Results : Regression models showed that IL-6 and NfL were significantly negatively associated with GM volume and that GM was positively associated with cognitive performance. The path analytic models indicated that age and cognitive performance are linked by GM in the hippocampus as well as several other regions previously associated with cognitive impairment, but not by NfL alone. Peripheral IL-6 was not associated with age in any of the path models. Conclusions : Results suggest that among healthy older adults, there are several GM regions that link age and cognitive performance. Notably, NfL alone is not a sufficient marker of brain changes associated with aging, inflammation, and cognitive performance.
... α-Syn is thought to function predominantly in the presynaptic terminal, suggesting that the impairment in eCB-dependent synaptic plasticity in Syn-tKO mice is likely due to a failure of CB1R signaling 49 . To test this hypothesis, we applied the CB1R agonist WIN55,212 (WIN; 2 µM) in acute brain slices. ...
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Two seemingly unrelated questions have long motivated studies in neuroscience: How are endocannabinoids, among the most powerful modulators of synaptic transmission, released from neurons? What are the physiological functions of synucleins, key contributors to Parkinson's Disease? Here, we report an unexpected convergence of these two questions: Endocannabinoids are released via vesicular exocytosis from postsynaptic neurons by a synuclein-dependent mechanism. Specifically, we find that deletion of all synucleins selectively blocks all endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wildtype but not of mutant α-synuclein. Loading postsynaptic neurons with endocannabinoids via patch-pipette dialysis suppressed presynaptic neurotransmitter release in wildtype but not in synuclein-deficient neurons, suggesting that the synuclein deletion blocks endocannabinoid release. Direct optical monitoring of endocannabinoid release confirmed the requirement of synucleins. Given the role of synucleins in vesicular exocytosis, the requirement for synucleins in endocannabinoid release indicates that endocannabinoids are secreted via exocytosis. Consistent with this hypothesis, postsynaptic expression of tetanus-toxin light chain, which cleaves synaptobrevin SNAREs, also blocked endocannabinoid-dependent plasticity and release. The unexpected finding that endocannabinoids are released via synuclein-dependent exocytosis assigns a function to synucleins and resolves a longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.
... Many of these essential protein targets have been reported to interact with cannabinoids and are associated with Groups I and II diseases. For example, Both CNR1 and CNR2 are members of the GPCR family and are largely involved in various activities and disorders of the central nervous system, including learning and memory, appetite, anxiety, depression, stroke, schizophrenia, multiple sclerosis, neurodegenerative diseases, epilepsy, pain, and addiction [50][51][52]. Several variations of CNR1 have been reported to be associated with Cannabis dependence [53][54][55]. ...
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This network-based pharmacology study intends to uncover the underlying mechanisms of cannabis leading to a therapeutic benefit and the pathogenesis for a wide range of diseases claimed to benefit from or be caused by the use of the cannabis plant. Cannabis contains more than 600 chemical components. Among these components, cannabinoids are well-known to have multifarious pharmacological activities. In this work, twelve cannabinoids were selected as active compounds through text mining and drug-like properties screening and used for initial protein-target prediction. The disease-associated biological functions and pathways were enriched through GO and KEGG databases. Various biological networks [i.e., protein-protein interaction, target-pathway, pathway-disease, and target-(pathway)-target interaction] were constructed, and the functional modules and essential protein targets were elucidated through the topological analyses of the networks. Our study revealed that eighteen proteins (CAT, COMT, CYP17A1, GSTA2, GSTM3, GSTP1, HMOX1, AKT1, CASP9, PLCG1, PRKCA, PRKCB, CYCS, TNF, CNR1, CNR2, CREB1, GRIN2B) are essential targets of eight cannabinoids (CBD, CBDA, Δ9-THC, CBN, CBC, CBGA, CBG, Δ8-THC), which involve in a variety of pathways resulting in beneficial and adverse effects on the human body. The molecular docking simulation confirmed that these eight cannabinoids bind to their corresponding protein targets with high binding affinities. This study generates a verifiable hypothesis of medical benefits and harms of key cannabinoids with a model which consists of multiple components, multiple targets, and multiple pathways, which provides an important foundation for further deployment of preclinical and clinical studies of cannabis.
... Although the literature is limited in aging adults, the findings are also consistent, with some preclinical research suggesting that young individuals might be more susceptible to the deleterious effects of THC as compared with older individuals [13]. In addition, it has been well documented that there are age-dependent changes in the endocannabinoid system (ECS) and that both cannabinoid receptors (CBR) and endocannabinoid (eCB) expression levels diminish with age [35][36][37][38]. Thus, our age group differences may be driven by differential expression of CBRs, specifically cannabinoid receptor type 1 (CB1) and eCB activity in brain regions governing executive function and reward. ...
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In recent years of expanding legalization, older adults have reported the largest increase in cannabis use of any age group. While its use has been studied extensively in young adults, little is known about the effects of THC in older adults and whether the risks of cannabis might be different, particularly concerning intoxication and cognition. The current study investigated whether age is associated with the deleterious effects of THC on cognitive performance and other behavioral measures before and after ad libitum self-administration of three different types of cannabis flower (THC dominant, THC + CBD, and CBD dominant). Age groups consisted of young adults (ages 21-25) and older adults (ages 55-70). Controlling for pre-use scores on all measures, the THC dominant chemovar produced a greater deleterious effect in younger adults compared with older adults in tests of learning and processing speed, whereas there were no differences between old and young in the effects of the other chemovars. In addition, the young group reported greater cannabis craving than the older group after using the THC chemovar. Consistent with some reports in the preclinical literature, the findings suggest that older adults may be less sensitive to the effects of THC on cognitive and affective measures.
... As discussed above, the endocannabinoid system plays a vital role in brain development, and CB1 receptors peak during adolescence. From adolescence through older adulthood, CB1 receptors decrease by about 50% (for review, see [74]). The loss of CB1 receptors and 2-AG in subcortical regions is associated with loss of gray matter density [75]. ...
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Purpose of Review This review examines the neurocognitive effects of cannabis and relevant developmental factors across adolescence (age 13–21), adulthood (21–65), and older adulthood (65 +). Recent Findings Cannabis use is robustly associated with poorer neurocognitive functioning; however, studies that carefully control for confounds have often not found any evidence for impairment. Notably, the endocannabinoid system may underly how cannabis use affects neurocognitive functions, including heightened vulnerability during adolescence. In contrast, the endocannabinoid system may underlie protective neurocognitive effects of cannabis in older adults. Notably, older adults have reported sharp increases in recent cannabis use. Summary As legalization increases the accessibility, variety, and potency of cannabis, strong empirical evidence is needed to understand its neurocognitive effects across the lifespan. In particular, rigorous study designs are needed to investigate the neurocognitive effects of cannabis, including among vulnerable populations (adolescents, older adults) and mediating (e.g., endocannabinoid system) and moderating factors (e.g., alcohol use).
... From a physiological point of view, the activation of cannabis receptors in the CNS modulates the adenylate cyclase activity, which in turn inhibits cyclic adenosine monophosphate accumulation, voltage-gated calcium and potassium channels and neurotransmitter release in presynaptic excitatory and inhibitory synapses [33]. For this reason, these receptors are indicated in many disorders affecting the brain, including several neurodegenerative disorders such as Huntington's disease, multiple sclerosis and Alzheimer's disease [34]. ...
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Historically, humans have used Cannabis sativa for both recreational and medical purposes. Nowadays, cannabis-based products have gained scientific interest due to their beneficial effects on several syndromes and illnesses. The biological activity of cannabinoids is essentially due to the interaction with the endocannabinoid system and zebrafish (Danio rerio) is a very well-known and powerful in vivo model for studying such specific interactions. The aim of the study was to investigate the effects of different doses of a Cannabis sativa whole extract (dissolved in DMSO) on zebrafish eggs hatchability, embryo post-hatching survival, larvae locomotion behavior and mRNA gene expression. The results showed the absence of toxicity and no significant differences were observed between treatments for both embryos hatching and survival rate. In addition, larvae exposed to the cannabis extract at the highest dose (containing 1.73 nM and 22.3 nM of THC and CBD, respectively) showed an increased locomotion compared to control and DMSO treated groups. Moreover, qRT-PCR analysis showed that the highest dosage of can-nabis induced an over-expression of cnr1 and cnr2 cannabinoid receptors. In conclusion, the ex-position of zebrafish larvae to the whole extract of Cannabis sativa showed no negative effects on embryo development and survival and enhanced the larvae locomotor performances. These findings may open to possible Cannabis sativa applications in human pharmacology, as well as other animal sector.
... Furthermore, PUFAs can be released from the plasmatic membrane via phospholipase A2 (PLA2). Free PUFAs are then metabolized into several regulators of inflammation (Buckley et al., 2013;Di Marzo et al., 2015;Serhan, 2014). Most pro-or anti-inflammatory PUFA metabolites are attributed to lipid mediators synthesized by oxygenation, hydroxylation, and peroxidation of AA, DHA and EPA, called eicosanoids (Arita, 2012) or other derivatives as resolvins, protectins or maresins (Chiurchiù et al., 2016;Serhan, 2017;Xian et al., 2016). ...
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Purpose: The retina has enormous lipids demands and must meet those needs. Retinal lipid homeostasis appears to be based on the symbiosis between neurons, Müller glial cells (MGC), and retinal pigment epithelium (RPE) cells, which can be impacted in several retinal diseases. The current research challenge is to better understand lipid-related mechanisms involved in retinal diseases, such as age-related macular degeneration (AMD) and glaucoma. Results: In a first axis, in vitro and focus on Müller glial cell, we aimed to characterize whether the 24S-hydroxycholesterol (24S-OHC), an overexpressed end-product of cholesterol elimination pathway in neural tissue and likely produced by suffering retinal ganglion cells in glaucoma, may modulate MGC membrane organization, such as lipid rafts, to trigger cellular signalling pathways related to retinal gliosis. We have found that lipid composition appears to be a key factor of membrane architecture, especially for lipid raft microdomain formation, in MGC. However, 24S-OHC did not appear to trigger retinal gliosis via the modulation of lipid or protein composition within lipid rafts microdomains. This study provided a better understanding of the complex mechanisms involved in the pathophysiology of glaucoma. On a second clinical ax, we focused on the lipid-related mechanisms involved in the dysfunction of aging RPE and the appearance of drusenoid deposits in AMD. Using the Montrachet population-based study, we intend to report the frequency of reticular pseudodrusen (RPD) and its ocular and systemic risk factors, particularly related to lipid metabolisms, such as plasma lipoprotein levels, carotenoids levels, and lipid-lowering drug intake. Our study showed that RPD was less common in subjects taking lipid-lowering drugs. Lipid-lowering drugs, such as statins, may reduce the risk of RPD through their effect on the production and function of lipoproteins. This observation highlights the potential role of retinal lipid trafficking via lipoproteins between photoreceptors and retinal pigment epithelium cells in RPD formation. Those findings have been complemented with preliminary results on the analysis of plasma fatty acid (FA) profile, a surrogate marker of short-term dietary lipid intake, according to the type of predominant drusenoid deposit, soft drusen or RPD, in age-related maculopathy. Conclusion: Further research on lipid metabolism in retinal diseases is warranted to better understand the pathophysiology of retinal diseases and develop new promising diagnostic, prognostic, and therapeutic tools for our patients.
... This cannabinoid is the major psychoactive ingredient in Cannabis sativa. It elicits its psychoactive effects by activating the cannabinoid receptor 1 (CB1), a main component of inhibitory synaptic feedback processes and synaptic plasticity, underlying learning and memory, reward, stress, and anxiety (Di Marzo et al., 2015;Lutz et al., 2015). ...
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Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ ⁹ -tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex ® . Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.
... Apart from opioid mechanisms, the second neuromodulatory system involving in the pathophysiology of pain that has recently raised particular interest for the development of new therapeutic strategies is the endocannabinoids system (ECS) that plays a key role in pain control. This system is integrated by the cannabinoid receptors, their endogenous ligands, and the enzymes involved in the synthesis and degradation of these ligands [38][39][40][41]. As stated above, experimental and clinical studies have shown the importance of the ACC in affective aspects of pain [9]. ...
Chapter
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The endogenous opioid and cannabinoid systems play a major role in the control of pain as well as in mood regulation, reward processing, and the development of addiction. Pain sensation is characterized as a complex experience, dependent on sensory processes but also on the activation of emotional operations in limbic brain areas. A network analysis suggested that there are broad-ranging, as well as specific changes with a focus on prefrontal limbic regions, the anterior cingulate cortex, anterior (agranular) insula, central amygdala, and other midbrain structures. This chapter provides an original account of behavioral aspects for the study of brain mechanisms of analgesia by widely used non-steroidal anti-inflammatory drugs in rodents' formalin test. It explains mechanisms of antinociception by these non-opioid drugs in one of the pain matrix key structures of brain limbic areas,-the anterior cingulate cortex,-with testing thermal and mechanical withdrawal reflexes in rats. In these experimental paradigms, the chapter presents a study of the roles of endogenous opioid and cannabinoid systems in brain descending pain control mechanisms.
... Endocannabinoid system (ECS) is known as a complex lipid signaling network involved in the modulation of various physiological and pathophysiological events [1]. It is part of the neuromodulatory system in the central and peripheral nervous system, and it is considered as a potential therapeutic target for nervous system diseases [2,3]. Recently, the activation of ECS has revealed beneficial effects in controlling neuronal excitability and epileptic activities [4][5][6]. ...
Article
Objective: Phytocannabinoids beyond the Δ9-tetrahy-drocannabinol have shown anticonvulsive effects. Also, alkylamides from Echinacea purpurea have been proved as cannabinomimetics. We examined the effect of the hydroalcoholic root extract of E. purpurea on pentylenetetrazol (PTZ)-induced tonic-clonic seizures and kindling model of epileptogenesis and the involvement of CB2 receptors as the mediator of this effect. Methods: Male Wistar rats (200 ± 20 g) were used. Single intraperitoneal (i.p.) injection of PTZ (80 mg/kg) was used to induce tonic-clonic seizures. The kindling model of epileptogenesis was induced by daily injections of PTZ (37 mg/kg; i.p. for 15 days). Latency and duration of the stages were monitored for analysis. The hydroalcoholic root extract of E. purpurea was injected (i.p.) 20 min before seizure induction at the doses of 10, 50, 100 and 200 mg/kg. CB2 receptor antagonist SR144528 was injected (0.1 mg/kg; i.p.) 20 min before the Echinacea injection. Results: In the tonic-clonic model, pretreatment with E. purpurea at the doses of 100 and 200 mg/kg significantly increased latencies to S2-S6, while it significantly decreased S6 duration and mortality rate. SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly prevented the effects of the extract on S4-S6 latencies. In the kindling model, E. purpurea at the doses of 100 and 200 mg/kg significantly delayed epileptogenesis and decreased mortality rate, while SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly blocked this effect of the extract. Conclusion: These findings revealed the anticonvulsive and antiepileptogenesis effects of the E. purpurea root extract, which can be mediated by CB2 receptors.
... The endocannabinoid system (ECS) is a widespread neuromodulatory network that plays an important role in the regulation of many cognitive and physiological processes by modulating neuronal activity [1]. The ECS appears to be of relevance as a therapeutic target in central nervous system (CNS) disorders, particularly in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), strokes, traumatic brain injury (TBI), pain, and epilepsy. ...
Article
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Polypharmacology breaks up the classical paradigm of “one-drug, one target, one disease” electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.
... been shown to be neuroprotective and attenuates macrophage/ microglial activation in mouse models of cerebral ischemia [34][35][36][37][38]. CB 2 R was also upregulated in other brain diseases with involvement of inflammation/microglia under chronic inflammation in neurodegenerative diseases such as Alzheimer's disease [39][40][41][42] and senescence-accelerated models [43] associated with amyloid-β deposits [33,[44][45][46][47][48][49][50]. ...
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Purpose: Stroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI). Procedures: Our recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. Results: mRNA expressions of inflammatory markers TNF-α, Iba1, MMP9 and GFAP, CNR2 were increased to 1.3-2.5 fold at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced to ca. 50 %. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. Conclusions: This study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.
... Physiological aging appears to be paralleled by changes in the brain endocannabinoid system [61]. Specifically, in older animals, a decline in the expression and activity of CB1R has been reported, together with alterations in the levels of synthetic and degrading enzymes. ...
Article
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Cannabis is still the most widely used illicit drug around the world. While its use has always been prevalent among adolescents, recent evidence suggests that its consumption is also increasing among other population groups, such as pregnant women and aged people. Given the known impact of cannabis on brain development and behavior, it is important to dissect the possible long-term impact of its use across different age groups, especially on measures of cognitive performance. Animal models of cannabinoid exposure have represented a fundamental tool to characterize the long-lasting consequences of cannabinoids on cognitive performance and helped to identify possible factors that could modulate cannabinoids effects in the long term, such as the age of exposure and doses administered. This scoping review was systematically conducted using PubMed and includes papers published from 2015 to December 2021 that examined the effects of cannabinoids, either natural or synthetic, on cognitive performance in animal models where exposure occurred in the prenatal period, during adolescence, or in older animals. Overall, available data clearly point to a crucial role of age in determining the long-term effect of cannabinoid on cognition, highlighting possible detrimental consequences during brain development (prenatal and adolescent exposure) and beneficial outcomes in old age. In contrast, despite the recent advances in the field, it appears difficult to clearly establish a possible role of dosage in the effects of cannabinoids on cognition, especially when the adolescent period is taken into account.
... For example, preclinical studies reveal decreased levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the aging mouse brain, and report that CB1 receptor binding peaks in puberty, remains stable early to mid-adulthood, and ultimately declines in older adulthood (Piyanova et al., 2015). Human studies have similarly revealed higher CB1 receptor binding in younger individuals relative to older adults (Di Marzo, Stella, & Zimmer, 2015). In addition, although few studies have examined cognition secondary to MC use in older adults, several animal studies highlight the potential for cannabis to improve cognition in this population (Weinstein & Sznitman, 2020), including one study demonstrating that administration of low-dose THC reversed age-related decline in older adult mice (Bilkei-Gorzo et al., 2017) While results from the current study are promising, findings must be considered given several limitations. ...
Article
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Objective: Cannabis use has increased dramatically across the country; however, few studies have assessed the long-term impact of medical cannabis (MC) use on cognition. Studies examining recreational cannabis users generally report cognitive decrements, particularly in those with adolescent onset. As MC patients differ from recreational consumers in motives for use, product selection, and age of onset, we assessed cognitive and clinical measures in well-characterized MC patients over 1 year. Based on previous findings, we hypothesized MC patients would not show decrements and might instead demonstrate improvements in executive function over time. Method: As part of an ongoing study, MC patients completed a baseline visit prior to initiating MC and evaluations following 3, 6, and 12 months of treatment. At each visit, patients completed a neurocognitive battery assessing executive function, verbal learning/memory, and clinical scales assessing mood, anxiety, and sleep. Exposure to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) was also quantified. Results: Relative to baseline, MC patients demonstrated significant improvements on measures of executive function and clinical state over the course of 12 months; verbal learning/memory performance generally remained stable. Improved cognitive performance was not correlated with MC use; however, clinical improvement was associated with higher CBD use. Analyses suggest cognitive improvements were associated with clinical improvement. Conclusions: Study results extend previous pilot findings, indicating that MC patients may exhibit enhanced rather than impaired executive function over time. Future studies should examine distinctions between recreational and MC use to identify potential mechanisms related to cognitive changes and the role of clinical improvement.
... The endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are signaling lipids that activate cannabinoid type-1 (CB1R) and type-2 (CB2R) receptors in the central nervous system and peripheral tissues (Zou and Kumar, 2018). CB1R is widely expressed in the brain and regulates numerous physiological processes, including pain, neuroprotection, cognitive functions, motor activity, and feeding behavior (Howlett et al., 2002;Kano et al., 2009;Di Marzo et al., 2015). In contrast, CB2R is primarily expressed in immune cells where it mediates the anti-inflammatory and immunosuppressive effects of eCBs (Ashton and Glass, 2007). ...
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The endocannabinoid (eCB) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are endogenous lipid neurotransmitters that regulate an array of physiological functions, including pain, stress homeostasis, and reward. Fatty acid-binding protein 5 (FABP5) is a key modulator of intracellular eCB transport and inactivation. Recent evidence suggests that FABP5 controls synaptic 2-AG signaling at excitatory synapses in the dorsal raphe nucleus. However, it is currently not known whether this function extends to other brain areas. To address this, we first profiled eCB levels across several brain areas in FABP5 knockout mice and wild-type controls and report that FABP5 deletion elevates AEA levels in the striatum, prefrontal cortex, midbrain, and thalamus, as well as midbrain 2-AG levels. The expression of eCB biosynthetic and catabolic enzymes was largely unaltered in these regions, although minor sex and region-specific changes in the expression of 2-AG catabolic enzymes were observed in female FABP5 KO mice. Robust FABP5 expression was observed in the striatum, a region where both AEA and 2-AG control synaptic transmission. Deletion of FABP5 impaired tonic 2-AG and AEA signaling at striatal GABA synapses of medium spiny neurons, and blunted phasic 2-AG mediated short-term synaptic plasticity without altering CB1R expression or function. Collectively, these results support the role of FABP5 as a key regulator of eCB signaling at excitatory and inhibitory synapses in the brain.
... While N-acylphosphotidylethanolamine-specific phospholipase D (NAPE-PLD) and calcium-dependent N-acyltransferase (NAT) are mainly responsible for AEA synthesis, α/β hydrolase domain-containing protein 4 (ABHD4) and fatty acid amide hydrolase (FAAH) contributes to its degradation. The 2-AG is mostly synthesized by diacylglycerol 2 of 18 lipase α (DAGLα) and degraded by monoacylglycerol lipase (MAGL) [1][2][3]. The presence of an active eCB system was detected as early as gestational day 14 in rat brains and was reported to undergo dynamic changes until the early postnatal development [4]. ...
Article
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Endocannabinoid (eCB) signaling is markedly decreased in the hippocampus (Hip) of aged mice, and the genetic deletion of the cannabinoid receptor type 1 (CB1) leads to an early onset of cognitive decline and age-related histological changes in the brain. Thus, it is hypothesized that cognitive aging is modulated by eCB signaling through CB1. In the present study, we detailed the changes in the eCB system during the aging process using different complementary techniques in mouse brains of five different age groups, ranging from adolescence to old age. Our findings indicate that the eCB system is most strongly affected in middle-aged mice (between 9 and 12 months of age) in a brain region-specific manner. We show that 2-arachidonoylglycerol (2-AG) was prominently decreased in the Hip and moderately in caudate putamen (CPu), whereas anandamide (AEA) was decreased in both Cpu and medial prefrontal cortex along with cingulate cortex (mPFC+Cg), starting from 6 months until 12 months. Consistent with the changes in 2-AG, the 2-AG synthesizing enzyme diacylglycerol lipase α (DAGLα) was also prominently decreased across the sub-regions of the Hip. Interestingly, we found a transient increase in CB1 immunoreactivity across the sub-regions of the Hip at 9 months, a plausible compensation for reduced 2-AG, which ultimately decreased strongly at 12 months. Furthermore, quantitative autoradiography of CB1 revealed that [3H]CP55940 binding markedly increased in the Hip at 9 months. However, unlike the protein levels, CB1 binding density did not drop strongly at 12 months and at old age. Furthermore, [3H]CP55940 binding was significantly increased in the lateral entorhinal cortex (LEnt), starting from the middle age until the old age. Altogether, our findings clearly indicate a middle-age crisis in the eCB system, which could be a potential time window for therapeutic interventions to abrogate the course of cognitive aging.
... The ECS has been widely studied in psychiatric disorders due to its capacity to act as a central nervous system (CNS) modulator in different neurophysiological processes (Review by Di Marzo et al., 2014). Several studies have investigated the role of the ECS in schizophrenia, suggesting that modulation of the ECS could be a novel potential therapeutic target for its treatment. ...
Chapter
Schizophrenia is a psychiatric disorder of neurodevelopmental origin that is thought to result from the combination of genetic and socioenvironmental factors. Several studies have linked the endocannabinoid system with the pathophysiology of schizophrenia. Here, we provide a brief overview of the role of the endocannabinoid system (ECS) in the context of biological processes relevant to schizophrenia, such as neurodevelopment, synaptic plasticity, and brain energy metabolism. We also discuss alterations related to the ECS in schizophrenia and current efforts in both in vivo and in vitro studies that have provided a better understanding of the functioning of this system in the context of the disorder. Finally, we highlighted the modulation of the ECS as a potential for discovering novel therapeutic targets, suggesting new avenues for future research in the field.
... The ECS has been widely studied in psychiatric disorders due to its capacity to act as a central nervous system (CNS) modulator in different neurophysiological processes (Review by Di Marzo et al., 2014). Several studies have investigated the role of the ECS in schizophrenia, suggesting that modulation of the ECS could be a novel potential therapeutic target for its treatment. ...
Chapter
Schizophrenia is a complex and heterogeneous neurodevelopmental psychiatric disorder characterized by a variety of symptoms classically grouped into three main domains: positive (hallucinations, delusions, and thought disorder) and negative symptoms (social withdrawal, lack of affect) and cognitive dysfunction (attention, working and episodic memory functions, and processing speed). This disorder places an immense emotional and economic pressure on the individual and society-at-large. Although the etiology of schizophrenia is not completely known, it is proposed to involve abnormalities in neurodevelopmental processes and dysregulation in the signaling mediated by several neurotransmitters, such as dopamine, glutamate, and GABA. Preclinical research using animal models are essential in our understanding of disease development and pathology as well as the discovery and advance of novel treatment choices. Here we describe rodent models for studying schizophrenia, including those based on the effects of drugs (pharmacological models), neurodevelopmental disruption, demyelination, and genetic alterations. The advantages and limitations of such models are highlighted. We also discussed the great potential of proteomic technologies in unraveling the molecular mechanism of schizophrenia through animal models.
... Another system in the BLA is the endocannabinoid system (Tan et al. 2011). Endocannabinoids are lipid-derived transmitters that can stimulate cannabinoid type-1 (Cb1) and cannabinoid type-2 (Cb2) receptors (Di Marzo et al. 2015;Pertwee 2006;Strangman et al. 1998). The Cb1 receptor is a membrane-related G-protein-coupled receptor, expressed broadly -but not exclusively -within the CNS (Ramikie & Patel 2012). ...
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The amygdala has emerged as the main brain center for the emotional affective dimension of pain and pain modulation. In the amygdala, orexin and cannabinoid receptors are expressed in relatively high concentrations. To investigate the possible interaction between the amygdala orexin and cannabinoid systems on the modulation of inflammatory pain, we conducted formalin, rotarod, and plethysmometer tests, as well as analyzing mRNA expression of orexin and cannabinoid receptors in male rats. The basolateral amygdala (BLA) was unilaterally implanted by a guide cannula. Our results showed that, compared to saline and DMSO/saline, intra-BLA microinjection of orexin-A (50 and 100 µM) decreased flinch response in the early phase, but not in the late phase of the formalin test. However, these injections had no significant effect on the mRNA expression level of BLA, orexin receptor type-1 (Orx1), and cannabinoid receptor type-1 (Cb1). Moreover, intra-BLA administration of Orx1 receptor antagonist (SB-334867; 50 nM) and Cb1 receptor antagonist (AM251; 250 and 500 nM) decreased flinch response only in the early phase of the formalin test as compared to the DMSO group. Although the intra-BLA infusion of orexin-A alone and along with SB-334867 or AM251 decreased flinch response in the early phase of the formalin test, intra-BLA co-microinjection of SB-334867/AM251/OrxA increased flinch response in both early and late phases of the formalin test when compared to the DMSO/OrxA group. Interestingly, in the SB-334867/AM251/OrxA group, the Cb1 receptor was upregulated in all groups in comparison to Orx1 receptors. Our results revealed an interaction between BLA, orexin-A, and Cb1 receptors in inducing anti-nociception in the formalin test.
... The endocannabinoid N-arachidonoyl-ethanolamine (AEA) is an endogenous lipid recognized to activate the cannabinoid receptors CB 1 and CB 2, as well as the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor [1][2][3][4]. As such, AEA is involved in numerous physiological responses, notably nociception, appetite and inflammation [5][6][7][8][9]. In addition to AEA, N-acyl-ethanolamines (NAEs) containing sixteen or plus carbons, together with their receptors including other TRP channels and G-protein-coupled receptors as well as peroxisome proliferator-activated receptors (PPARs), are part of the endocannabinoidome [10]. ...
Article
N-Arachidonoyl-ethanolamine (AEA) is an endocannabinoid (eCB) and endogenous lipid mimicking many of the effects of Δ⁹-tetrahydrocannabinol, notably on brain functions, appetite, pain and inflammation. The eCBs and eCB-like compounds contain fatty acids, the main classes being the monoacylglycerols and the N-acyl-ethanolamines (NAEs). Thus, each long chain fatty acid likely exists under the form of a monoacylglycerol and NAE, as it is the case for arachidonic acid (AA) and linoleic acid (LA). Following their biosynthesis, AA and AEA can be further metabolized into additional eicosanoids, notably by the 15-lipoxygenase pathway. Thus, we postulated that NAEs possessing a 1Z,4Z-pentadiene motif, near their omega end, would be transformed into their 15-lipoxygenase metabolites. As a proof of concept, we investigated N-linoleoyl-ethanolamine (LAE). We successfully synthesized LEA and LEA-d4 as well as their 15-lipoxygenase-derived derivatives, namely 13-hydroxy-9Z,11E-octadecadienoyl-N-ethanolamine (13-HODE-EA) and 13-HODE-EA-d4, using Novozyme 435 immobilized on acrylic resin and soybean lipoxygenase respectively. We also show that both human 15-lipoxygenase-1 and -2 can biosynthesize 13-HODE-EA. Co-incubation of LEA and LA with either human 15-lipoxygenase led to the biosynthesis of 13-HODE-EA and 13-HODE in a ratio equal to or greater than 3:1, indicating that LEA is preferred to LA by these enzymes. Finally, we show that 13-HODE-EA is found in human saliva and skin and is a weak although selective TRPV1 agonist. The full biological importance of 13-HODE-EA remains to be explored.
... Returning to our idea that the eCB tone may be saturating in females, we tested the effects of MJN110 or AM251 in a group of older females, 8 months of age. Previous literature has suggested that eCB signaling may decrease with age (Bilkei-Gorzo, 2012; Di Marzo et al., 2015). We suspected that with further maturation, the eCB tone in females would decrease. ...
Preprint
Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in developing and adult mice. We find that eCBs are downregulated in response to acute sleep deprivation in juvenile mice, while in young adults eCBs are upregulated during the sleep phase in a circadian manner. Next we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
... In mice, CB 2 R was detected in the astroglia of the nucleus accumbens and ventral tegmental area [79]. Complementary studies show that this expression is significantly upregulated in the presence of certain types of lesions in both reactive microglia and activated astrocytes [84][85][86], which has served to refute its role in diseases in which the neuroinflammatory component is important, such as schizophrenia (for review [87,88]). ...
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Since the identification and cloning of the cannabinoid receptor 2 (CB2R), several studies focused on the characterization of its physiological and pathological role. Initially, CB2R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB2R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB2R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB2R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB2R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders.
... To explore the cellular and molecular mechanisms through which cannabinoid-induced effects might favorably impact the prognosis in MS, additional experimental observational studies are required to investigate the exact types of receptors and signaling pathways that could reverse injury to oligodendrocytes and neurons and promote CNS tissue repair, regeneration, and remyelination [152,153]. ...
Article
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Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~1:1 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term.
... In the nematode, Lucanic et al. concluded that the TOR-pathway might control NAE levels in response to nutrient intake and that reduced NAE signaling is a component of CR-mediated lifespan extension [27]. On the other hand, there is evidence that NAEs activate mTOR [54,55] and AMPK signaling in renal proximal tubular cells [56] as well as hepatocytes [57]. ...
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Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.
... Furthermore, the endocannabinoid system could undergo a progressive age-related deficit, accelerating cognitive decline [224]. These hallmarks of brain aging could be attenuated by ω-3 PUFA supplementation [222,225]. ...
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Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.
... Upregulation of brain CB 2 R expression is reported under acute in ammation such as ischemic stroke, and related to lesion extension in the penumbra and subsequent functional recovery [29]. Treatment with CB 2 R agonists has been shown to be neuroprotective and attenuates macrophage/microglial activation in the mouse models of cerebral ischemia [29,[42][43][44][45]. CB 2 R is also upregulated in other brain diseases with involvement of in ammation/microglia under chronic in ammation in neurodegenerative diseases such as Alzheimer's disease [30][31][32][33] and senescenceaccelerated models [34], associated with amyloid-b deposits[28, [35][36][37][38][39][40][41]. ...
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Background and purposeBrain ischemia is one of the most important pathologies of the central nervous system. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptors (CB 2 R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [ ¹⁸ F]RoSMA-18-d6, and structural imaging by magnetic resonance imaging (MRI). Methods Our recently developed CB 2 R PET tracer [ ¹⁸ F]RoSMA-18-d6 was used for imaging the neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB 2 R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [ ¹⁸ F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T 2 -weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. ResultsmRNA expressions of inflammatory markers TNF-a , Iba1, MMP9 and GFAP, CNR2 were increased at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced. Reduced [ ¹⁸ F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [ ¹⁸ F]RoSMA-18-d6 in ex-vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in-vivo specificity of [ ¹⁸ F]RoSMA-18-d6 was confirmed only in the CB 2 R-rich spleen. Conclusions This study revealed an increased [ ¹⁸ F]RoSMA-18-d6 measure of CB 2 R and a reduced [ ¹⁸ F]FDG measure of CMRglc in ischemic striatum of tMCAO mice at subacute stage. [ ¹⁸ F]RoSMA-18-d6 might be a promising PET tracer for detecting CB 2 R alterations in animal models of neuroinflammation without neuronal loss.
... AEA is synthesized by the N-acylphosphatidylethanolamine specific phospholipase D (NAPE-PLD) that hydrolyzes AEA [38,39]. AEA is quickly uptaken by the eCBs membrane transporter (EMT) [40]. AEA is degraded by fatty acid amide hydrolase (FAAH), present in the brain at postsynaptic location [41,42]. ...
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... Anandamide and 2-AG are produced in postsynaptic neurons. Anandamide is produced in two steps from the membrane phospholipid, phosphatidylethanolamine, formed by a calcium-dependent enzyme N-acyltransferase N-arachidonoyl-phosphatidylethanolamine, followed by hydrolysis by a selective phospholipase D of N-arachidonoylethanolamine to form N-arachidonoylethanolamine [47][48][49][50][51]. Anandamide is hydrolyzed in postsynaptic neurons through the action of fatty acid amide hydrolase (FAAH) [52]. ...
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... In the nematode, Lucanic et al. concluded, that the TOR-pathway might control NAE levels in response to nutrient intake and that reduced NAE signaling is a component of CR-mediated lifespan extension [23]. On the other hand, there is evidence that NAEs activate mTOR [49,50] and AMPK signaling in renal proximal tubular cells [51] as well as hepatocytes [52]. ...
Preprint
Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents AKI can be prevented effectively through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans) longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, in particular arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.
... 19 Alternatively, the rise in Aβ 1−42 level is also observed due to activation of the EP4 receptor by prostaglandin E2 (PGE2), followed by activation of mitogenactivated protein kinase (MAPK) and extracellular signalregulated kinase (ERK), thereby resulting in neuroinflammation caused by the overproduction of IL-1β and TNF-α. 20,21 However, modulation of the neuroinflammatory pathology of Alzheimer's disease can also be achieved by the inhibition of MAGL and FAAH. MAGL inhibitors upregulate the levels of 2-AG, which binds with the CB1 receptor and suppresses the COX-2 enzyme, simultaneously declining PGE2, ERK1/2, p38MAPK, and NF-κB in neurons. ...
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Chapter
Endocannabinoids (eCBs) are endogenous lipids able to bind to cannabinoid receptors, the primary molecular targets of the cannabis (Cannabis sativa) active principle Δ9-tetrahydrocannabinol. During the last 20 years, several N-acylethanolamines and acylesters have been shown to act as eCBs, and a complex array of receptors, metabolic enzymes, and transporters (that altogether form the so-called “eCB system”) has been shown to finely tune their manifold biological activities. It appears now urgent to develop methods and protocols that allow to assay in a specific and quantitative manner the distinct components of the eCB system and that can properly localize them within the cell. A brief overview of eCBs and of the proteins that bind, transport, and metabolize these lipids is presented here, in orderto put in a better perspective, the relevance of methodologies that help to disclose molecular details of eCB signaling in health and disease. Proper methodological approaches form also the basis for a more rationale and effective drug design and therapeutic strategy to combat human disorders.Key wordsAnandamide2-ArachidonoylglycerolEnzyme assaysImmunochemical assaysIntracellular traffickingLocalizationMetabolic routesOxidative pathwaysReceptor binding assaysSignal transduction
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Introduction: In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes. Material and methods: The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English. Results: The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies. Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies. Conclusion: Current shortcomings in understanding the benefits of cannabis or hemp products are limited due to pharmacological and clinical effects not being predictable, while marketed products vary greatly in phytocompounds warrant further empirical investigation. Given the healthcare challenges to manage acute and chronic pain, this review highlights both cannabis and CBD-hemp extracts to help identify the therapeutic application for patient populations suffering from anxiety, inflammation, and dental pain.
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The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.
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The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The central nervous system produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that a moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because eCBs are biosynthesized from PUFAs. The primary eCB metabolites are derived from arachidonic acid, a 20:4n–6 (ω-6) PUFA, and the n–3 (ω-3) PUFAs, EPA and DHA. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulating appetite, influencing energy metabolism, supporting the immune system, and facilitating neuroplasticity. A diet containing different essential n–6 and n–3 PUFAs will dominate the formation of specific eCBs, and subsequently their actions as ligands for CB1 and CB2. The eCBs also function as substrates for cyclooxygenase enzymes, including potential substrates for the oxylipins (OxLs), which can be proinflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications for exercise responses via synthesis of eCBs and their effects on neuroinflammation. Neurotrophins also participate in interactions between diet and the eCBs, specifically brain-derived neurotrophic factor (BDNF). BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will describe the role of PUFAs in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence for exercise effects on eCBs, and describe eCB and BDNF actions on neuroplasticity.
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Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids
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Δ9-Tetrahydrocannabinol is the main psychoactive component of cannabis and cannabidiol is purportedly responsible for many of the medicinal benefits. The effects of Δ9-tetrahydrocannabinol and cannabidiol in younger populations have been well studied; however, motor function, cognitive function, and cerebral glucose metabolism in older adults have not been extensively researched. The purpose of this study was to assess differences in cognitive function, motor function, and cerebral glucose metabolism (assessed via [18F]-fluorodeoxyglucose positron emission tomography) in older adults chronically using Δ9-tetrahydrocannabinol, cannabidiol, and non-using controls. Eight Δ9-tetrahydrocannabinol users (59.3 ± 5.7 years), five cannabidiol users (54.6 ± 2.1 years), and 16 non-users (58.2 ± 16.9 years) participated. Subjects underwent resting scans and performed cognitive testing (reaction time, Flanker Inhibitory Control and Attention Test), motor testing (hand/arm function, gait), and balance testing. Δ9-tetrahydrocannabinol users performed worse than both cannabidiol users and non-users on the Flanker Test but were similar on all other cognitive and motor tasks. Δ9-tetrahydrocannabinol users also had lower global metabolism and relative hypermetabolism in the bilateral amygdala, cerebellum, and brainstem. Chronic use of Δ9-tetrahydrocannabinol in older adults might negatively influence inhibitory control and alter brain activity. Future longitudinal studies with larger sample sizes investigating multiple Δ9-tetrahydrocannabinol:cannabidiol ratios on functional outcomes and cerebral glucose metabolism in older adults are necessary.
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Introduction: Fatty acid amide hydrolase (FAAH) is one of the main terminating enzymes of the endocannabinoid system (ECS). Since being discovered in 1996, the modulation of FAAH has been viewed as a compelling alternative strategy to obtain the beneficial effect of the ECS. With a considerable amount of FAAH-related publication over time, the next step would be to comprehend the proximity of this evidence for clinical application. Objective: This review intends to highlight the rationale of FAAH modulation and provide the latest evidence from clinical studies. Methods: Publication searches were conducted to gather information focused on FAAH-related clinical evidence with an extension to the experimental research to understand the biological plausibility. The subtopics were selected to be multidisciplinary to offer more perspective on the current state of the arts. Discussion: Experimental and clinical studies have demonstrated that FAAH was highly expressed not only in the central nervous system but also in the peripheral tissues. As the key regulator of endocannabinoid signaling, it would appear that FAAH plays a role in the modulation of mood and emotional response, reward system, pain perception, energy metabolism and appetite regulation, inflammation, and other biological processes. Genetic variants may be associated with some conditions such as substance/alcohol use disorders, obesity, and eating disorder. The advancement of functional neuroimaging has enabled the evaluation of the neurochemistry of FAAH in brain tissues and this can be incorporated into clinical trials. Intriguingly, the application of FAAH inhibitors in clinical trials seems to provide less striking results in comparison with the animal models, although some potential still can be seen. Conclusion: Modulation of FAAH has an immense potential to be a new therapeutic candidate for several disorders. Further exploration, however, is still needed to ensure who is the best candidate for the treatment strategy.
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Although ataxia is associated with cerebellar dysfunction, little is known about the effects of ataxia on Purkinje cell electrophysiological properties. Here, we evaluated these parameters in cerebellar vermis brain slices. Purkinje cells were exposed to aCSF (control) or to 1 mM 3-acetyl pyridine (3-AP) in the recording chamber. Effects of a cannabinoid agonist (WIN; 7.5 nmol), and a cannabinoid antagonist (AM; 20 nmol) were evaluated under both conditions. Exposure to 3-AP induced dramatic changes in cellular excitability that likely would affect Purkinje cell output. In whole-cell current clamp recordings, 3-AP exposed Purkinje cells demonstrated a significantly higher frequency of action potentials, a larger afterhyperpolarization (AHP), and a larger rebound of action potentials. In addition, 3-AP caused a significant decrease in the interspike interval (ISI), half-width, and decreased the first spike latency. Remarkably, the action potential frequency, AHP amplitude, rebound, ISI, action potential halfwidth, and first spike latency were no longer different from controls in 3-AP cells treated with AM. Sag percentage, on the other hand, showed no significant difference under any treatment condition indicating that cannabinoids' actions on ataxia-mediated Purkinje cell changes may not include effects on neuronal excitability through changes of Ih. These data show that cannabinoid antagonists reduce the excitability of Purkinje cells in an ex vivo model of ataxia and suggest their potential as therapeutics in cerebellar dysfunctions.
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Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.
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The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.
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Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associates impaired autophagy, increased activity in the endocannabinoid system and upregulation of suppressor of cytokine signaling (SOCS)-3 protein expression during intestinal inflammatory states. We have investigated whether these three processes are linked. By assessing the impact of phyto-cannabinoid cannabidiol (CBD), synthetic cannabinoid (ACEA) and endocannabinoid (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated CaCo2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid receptor (CB)-1 mediated. In contrast, CBD was able to bypass both the CB1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking both early and late autophagy. In conclusion, the regulatory protein, SOCS3, is itself regulated by autophagy and cannabinoids play a role in this process, which could be important when considering therapeutic applications for the cannabinoids in inflammatory conditions.
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The long-term use of levodopa (L-DOPA) in Parkinson's disease (PD) results in the development of abnormal involuntary movements called L-DOPA-induced dyskinesias. Increasing evidences suggest that the endocannabinoid system may play a role in the modulation of dyskinesias. In this work, we assessed the antidyskinetic effect of the endocannabinoid analog oleoylethanolamide (OEA), an agonist of PPARα and antagonist of TRPV1 receptors. We used a hemiparkinsonian model of PD in mice with a 6-OHDA striatal lesion. A chronic L-DOPA treatment developed intense axial, forelimb and orolingual dyskinetic symptoms, as well as contralateral rotations. Treatment with OEA reduced all these symptoms without reducing motor activity or the therapeutic motor effects of L-DOPA. Moreover, the OEA-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of dyskinesia. OEA reduced FosB striatal overexpression and phosphoacetylation of histone 3, both molecular markers of L-DOPA-induced dyskinesias. We found that OEA antidyskinetic properties were mediated by a TRPV1 receptor, as pretreatment with capsaicin, a TRPV1 agonist, blocked OEA antidyskinetic actions, as well as the reduction in FosB- and pAcH3-overexpression induced by L-DOPA. This study supports the hypothesis that the endocannabinoid system plays an important role in the development and expression of dyskinesias and might be an effective target for the treatment of L-DOPA-induced dyskinesias. Importantly, there was no development of tolerance to OEA in any of the parameters we examined, which has important implications for the therapeutic potential of drugs targeting the endocannabinoid system.
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During brain development, neurogenesis is precisely regulated by the concerted action of intrinsic factors and extracellular signalling systems that provide the necessary niche information to proliferating and differentiating cells. A number of recent studies have revealed a previously unknown role for the endocannabinoid (ECB) system in the control of embryonic neuronal development and maturation. Thus, the CB(1) cannabinoid receptor in concert with locally produced ECBs regulates neural progenitor (NP) proliferation, pyramidal specification and axonal navigation. In addition, subcellularly restricted ECB production acts as an axonal growth cone signal to regulate interneuron morphogenesis. These findings provide the rationale for understanding better the consequences of prenatal cannabinoid exposure, and emphasize a novel role of ECBs as neurogenic instructive cues involved in cortical development. In this review the implications of altered CB(1)-receptor-mediated signalling in developmental disorders and particularly in epileptogenesis are briefly discussed.
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Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.